Communications
DOI: 10.1002/anie.201104516
Total Synthesis
Total Synthesis of Sialic Acid by a Sequential Rhodium-Catalyzed
Aziridination and Barbier Allylation of d-Glycal**
Rujee Lorpitthaya, Sharad B. Suryawanshi, Siming Wang, Kalyan Kumar Pasunooti,
Shuting Cai, Jimei Ma, and Xue-Wei Liu*
À
Aminoglycosides form a large class of clinically important
antibiotics with a broad antibacterial spectrum, particularly
against Gram-positive and Gram-negative pathogens.[1] The
biologically important carbohydrates in prokaryotic and
eukaryotic glycoconjugates are mainly comprised of 2-
amino-2-deoxyglycopyranosides.[2] The synthesis
of 2-amino-2-deoxypyranoside residues is chal-
lenging in two ways: the selective functionaliza-
tion of the nitrogen moiety at the C2-position,
and the formation of the glycosidic bond with
appropriate glycosyl acceptors. Nowadays, gly-
cals are often employed as versatile starting
materials for such syntheses. Numerous methods
have been developed for the direct introduction
of a nitrogen substituent at the C2-position of
glycals. These approaches involve inter- or intra-
molecular addition of a nitrogen atom to a glycal
scaffold, which generates an aziridine intermedi-
ate, followed by ring opening with a nucleophile.
These methods have been developed as general
pathways to generate 2-amino sugars.[3–5]
We herein describe a remarkable C C coupling reaction in
the sequential rhodium-catalyzed aziridination and Barbier
allylation or propargylation at the anomeric position of
d-glucal (Scheme 1). The reaction proceeded selectively to
form an eight-membered [1,2,3]-oxathiazocane-2,2-dioxide in
Over the years, our research has focused on
Scheme 1. One-pot, rhodium-catalyzed aziridination and indium-mediated allylation/
propargylation.
developing new synthetic methods for construct-
ing novel frameworks on sugar molecules, and
applying these methods to the synthesis of
natural products.[6] We have developed an intra-
molecular version of a rhodium-catalyzed addition of a
nitrene to a glycal scaffold. Specifically, the diastereofacial
preference of the nitrogen atom transfer process is controlled
by the position of a sulfamate ester moiety on the glycal
molecule. This causes the glycosyl acceptor to attack the
anomeric carbon atom on the opposite face of the sugar ring
to the sulfamoyloxy group.[7] We have a strong interest in
utilizing our protocol to synthesize the sialic acid N-acetyl-
neuraminic acid (Neu5Ac; 6) by direct C-aminoglycosylation.
a single step. Moreover, we demonstrate that a range of
nucleophiles can be used with this method. The total synthesis
of Neu5Ac and a protected derivative is also described.
Sulfamate ester 1 was prepared from tri-O-acetyl glucal[7a]
and treated with PhIO, MgO, and rhodium(II) trifluoroacet-
amide ([Rh2(tfacam)4]; 5 mol%) in CH2Cl2 at room temper-
ature, under N2. This reaction generated a nitrene in situ,
=
which added intramolecularly to the C C bond of the glycal.
Trapping the resulting transient aziridine 2 with an appro-
priate carbon nucleophile was critical. Barbier allylation or
propargylation has emerged as a powerful method for
[*] Dr. R. Lorpitthaya, Dr. S. B. Suryawanshi, S. Wang, K. K. Pasunooti,
S. Cai, Dr. J. Ma, Prof. Dr. X.-W. Liu
[8]
À
forming C C bonds; therefore, we applied this reaction in
our synthetic system.
Division of Chemistry and Biological Chemistry
School of Physical & Mathematical Sciences
Nanyang Technological University
21 Nanyang Link, Singapore 637371 (Singapore)
E-mail: xuewei@ntu.edu.sg
The initial investigation was focused on optimizing the
metal-mediated allylation[9] of 2. The results are summarized
in Table 1. Allylmagnesium bromide was very reactive with 2;
however, no coupled products were obtained (Table 1,
entry 1). Other metal–allyl reagents prepared from In, Sn,
and Zn were examined under the same reaction conditions.
Indeed, when 2 was treated with allyl bromide in the presence
of In metal in THF, a coupling reaction occurred and
oxathiazocane 7 was obtained in 72% yield (Table 1,
entry 2). Attempts were made to optimize the reaction
[**] We thank Prof. Francois Mathey and Prof. Koichi Narasaka for
fruitful discussions. We also thank Dr. Yong Xin Li for X-ray analyses
and gratefully acknowledge Nanyang Technological University
(NTU; RG 50/08) and the Ministry of Health (MOH; NMRC/
H1N1R/001/2009) Singapore for financial support.
Supporting information for this article is available on the WWW
12054
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 12054 –12057